Angela R. McLean

Theoretical Ecology: Principles and Applications

1. Introduction 2. How Populations Cohere: Five Rules for Cooperation 3. Single species dynamics 4. Metapopulations and Their Spatial Dynamics 5. Predator Prey Interactions 6. Plant Population dynamics 7. Interspecific Competition and Multispecies Coexistence 8. Diversity and stability in ecological communities 9. Community: Patterns 10. Dynamics of Infectious Diseases 11. Fisheries 12. A Doubly Green Revolution 13. Conservation Biology 14. Climate Change and Conservation Biology 15. Unanswered Questions and why they Matter

The intrinsic transmission dynamics of tuberculosis epidemics.

In developed countries the major tuberculosis epidemics declined long before the disease became curable in the 1940s. We present a theoretical framework for assessing the intrinsic transmission dynamics of tuberculosis. We demonstrate that it takes one to several hundred years for a tuberculosis epidemic to rise, fall and reach a stable endemic level. Our results suggest that some of the decline of tuberculosis is simply due to the natural behaviour of an epidemic. Although other factors must also have contributed to the decline, these Causal factors were constrained to operate within the slow response time dictated by the intrinsic dynamics.

Persistent HIV-1 replication maintains the tissue reservoir during therapy

Lymphoid tissue is a key reservoir established by HIV-1 during acute infection. It is a site associated with viral production, storage of viral particles in immune complexes, and viral persistence. Although combinations of antiretroviral drugs usually suppress viral replication and reduce viral RNA to undetectable levels in blood, it is unclear whether treatment fully suppresses viral replication in lymphoid tissue reservoirs. Here we show that virus evolution and trafficking between tissue compartments continues in patients with undetectable levels of virus in their bloodstream. We present a spatial and dynamic model of persistent viral replication and spread that indicates why the development of drug resistance is not a foregone conclusion under conditions in which drug concentrations are insufficient to completely block virus replication. These data provide new insights into the evolutionary and infection dynamics of the virus population within the host, revealing that HIV-1 can continue to replicate and replenish the viral reservoir despite potent antiretroviral therapy.

Stimulation of HIV-specific cellular immunity by structured treatment interruption fails to enhance viral control in chronic HIV infection

Potent antiretroviral therapy (ART) suppresses HIV-1 viral replication and results in decreased morbidity and mortality. However, prolonged treatment is associated with drug-induced toxicity, emergence of drug-resistant viral strains, and financial constraints. Structured therapeutic interruptions (STIs) have been proposed as a strategy that could boost HIV-specific immunity, through controlled exposure to autologous virus over limited time periods, and subsequently control viral replication in the absence of ART. Here, we analyzed the impact of repeated STIs on virological and immunological parameters in a large prospective STI study. We show that: (i) the plateau virus load (VL) reached after STIs correlated with pretreatment VL, the amount of viral recrudescence during the treatment interruptions, and the off-treatment viral rebound rate; (ii) the magnitude and the breadth of the HIV-specific CD8+ T lymphocyte response, despite marked interpatient variability, increased overall with STI. However, the quantity and quality of the post-STI response was comparable to the response observed before any therapy; (iii) individuals with strong and broad HIV-specific CD8+ T lymphocyte responses at baseline retained these characteristics during and after STI; (iv) the increase in HIV-specific CD8+ T lymphocyte frequencies induced by STI was not correlated with decreased viral set point after STI; and (v) HIV-specific CD4+ T lymphocyte responses increased with STI, but were subsequently maintained only in patients with low pretreatment and plateau VLs. Overall, these data indicate that STI-induced quantitative boosting of HIV-specific cellular immunity was not associated with substantial change in viral replication and that STI was largely restoring pretherapy CD8+ T cell responses in patients with established infection.

A restatement of the natural science evidence base concerning neonicotinoid insecticides and insect pollinators

There is evidence that in Europe and North America many species of pollinators are in decline, both in abundance and distribution. Although there is a long list of potential causes of this decline, there is concern that neonicotinoid insecticides, in particular through their use as seed treatments are, at least in part, responsible. This paper describes a project that set out to summarize the natural science evidence base relevant to neonicotinoid insecticides and insect pollinators in as policy-neutral terms as possible. A series of evidence statements are listed and categorized according to the nature of the underlying information. The evidence summary forms the appendix to this paper and an annotated bibliography is provided in the electronic supplementary material.

Imperfect vaccines and herd immunity to HIV

A number of prophylactic vaccines against human immunodeficiency virus (HIV) have passed through phase I clinical trials, and phase II clinical trials are now being planned. These vaccines are not expected to be perfect and might fail in a number of different ways. This paper shows how to equate different aspects of imperfection in a prophylactic vaccine in terms of impact upon levels of herd immunity, and hence upon the vaccine coverage required for eradication. Such comparisons reveal that an otherwise perfect vaccine that gives protection which wanes with a half-life of 10 years is only as good as a vaccine that works in 30% of people giving them complete, lifelong protection. The paper goes on to compare predicted patterns of seroconversion that would be observed in clinical trials and in community-wide vaccination campaigns for vaccines that confer the same levels of herd immunity but are imperfect in different ways.

Inefficient Cytotoxic T Lymphocyte–Mediated Killing of HIV-1–Infected Cells In Vivo

Understanding the role of cytotoxic T lymphocytes (CTLs) in controlling HIV-1 infection is vital for vaccine design. However, it is difficult to assess the importance of CTLs in natural infection. Different human leukocyte antigen (HLA) class I alleles are associated with different rates of progression to AIDS, indicating that CTLs play a protective role. Yet virus clearance rates following antiretroviral therapy are not impaired in individuals with advanced HIV disease, suggesting that weakening of the CTL response is not the major underlying cause of disease progression and that CTLs do not have an important protective role. Here we reconcile these apparently conflicting studies. We estimate the selection pressure exerted by CTL responses that drive the emergence of immune escape variants, thereby directly quantifying the efficiency of HIV-1–specific CTLs in vivo. We estimate that only 2% of productively infected CD4 + cell death is attributable to CTLs recognising a single epitope. We suggest that CTLs kill a large number of infected cells (about 10 7) per day but are not responsible for the majority of infected cell death.

Competition between zidovudine-sensitive and zidovudine-resistant strains of Hiv

ObjectiveTo investigate competitive interactions between zidovudine-sensitive and resistant strains of HIV within the context of host-parasite population dynamic interactions between CD4 + cells and HIV. DesignA mathematical model of the population dynamics of CD4 + cells, sensitive HIV and resistant HIV is developed. MethodsThe model is analysed numerically and analytically and model predictions are compared with previously published data on population dynamics of HIV and CD4 + cells in patients receiving zidovudine. A threshold result describing the critical dose of zidovudine above which resistant HIV will out-compete sensitive HIV is derived, as are expressions describing the critical effective doses for the eradication of sensitive and resistant strains. Numerical simulations of the dynamics of the shift from the pre-treatment, equilibrium to the treatment equilibrium are presented and an analytic expression approximating the time taken until virus growth restarts is derived. ResultsIt is shown that competition between strains of virus is the important factor determining which type of virus will eventually start to grow during the course of zidovudine treatment, but host-parasite interactions are the important determinant of when viral resurgence occurs. ConclusionsAlthough resistant strains are observed after prolonged treatment with zidovudine, this model suggests that it is the growing supply of uninfected CD4 + cells which causes the eventual upsurge in viral burden.

Effective T-Cell Responses Select Human Immunodeficiency Virus Mutants and Slow Disease Progression

ABSTRACT The possession of some HLA class I molecules is associated with delayed progression to AIDS. The mechanism behind this beneficial effect is unclear. We tested the idea that cytotoxic T-cell responses restricted by advantageous HLA class I molecules impose stronger selection pressures than those restricted by other HLA class I alleles. As a measure of the selection pressure imposed by HLA class I alleles, we determined the extent of HLA class I-associated epitope variation in a cohort of European human immunodeficiency virus (HIV)-positive individuals (n = 84). We validated our findings in a second, distinct cohort of African patients (n = 516). We found that key HIV epitopes restricted by advantageous HLA molecules (B27, B57, and B51 in European patients and B5703, B5801, and B8101 in African patients) were more frequently mutated in individuals bearing the restricting HLA than in those who lacked the restricting HLA class I molecule. HLA alleles associated with clinical benefit restricted certain epitopes for which the consensus peptides were frequently recognized by the immune response despite the circulating viruss being highly polymorphic. We found a significant inverse correlation between the HLA-associated hazard of disease progression and the mean HLA-associated prevalence of mutations within epitopes (P = 0.028; R2 = 0.34). We conclude that beneficial HLA class I alleles impose strong selection at key epitopes. This is revealed by the frequent association between effective T-cell responses and circulating viral escape mutants and the rarity of these variants in patients who lack these favorable HLA class I molecules, suggesting a significant pressure to revert.

The regulation of malaria parasitaemia: parameter estimates for a population model.

Classical studies of non-immune individuals infected with Plasmodium falciparum reveal that the infection may be regulated for long periods at a relatively stable parasite density, despite the enormous growth potential of a parasite that continually replicates within host erythrocytes. This suggests that the parasite population may be controlled by density-dependent mechanisms, and in theory the most obvious of these is competition between parasites for host erythrocytes. Here we evaluate the role of this mechanism in the regulation of parasitaemia, by modelling the basic population interaction between parasites and erythrocytes in a form that allows all the essential parameters to be estimated from clinical data. Our results show that competition cannot account for the total regulation of P. falciparum, but when combined with immune mechanisms it may play a more important role than is generally supposed. Further analysis of the model indicates that in the long term, parasite replication at low parasite densities can contribute significantly to the high degree of anaemia observed in natural infection, a conclusion which is not obvious from simple clinical observation.